Inflammatory reactions are caused by bacteria, viruses, and other pathogens and by trauma, foreign matter, etc. They are immunoreactions where granulocytes, monocytes, lymphocytes, and other immune cells expel pathogens or injured tissues or foreign materials. Dermatitis is an acute or chronic inflammation of the skin, and in particular, there has been a remarkable rise in atopic dermatitis in recent year, which is becoming a major problem.
Atopic dermatitis is a chronic disease in which eczema with itch is the major condition, with exacerbation and remission observed by turns. In most cases, the patient or his or her family has a history of cnidosis or allergic rhinitis and bronchial asthma and other allergic ailments (J. Allergy Clin. Immunol. 104, S123, 1999). The symptoms of atopic dermatitis are diverse and the causes are still unclear, but it is believed that the disease is elicted mainly by various natural substances including ticks, hair, feathers, bacteria and mycetes, or foods including eggs, milk, or synthetic products including chemical fibers and detergents, etc. It is also pointed out that the disorder in the barrier function of the skin due to dry skin plays an important role in atopic dermatitis.
The mechanism of onset of atopic dermatitis is still not clear. It has been thought that the type I allergic reaction (immediate allergic reaction), in which IgE and mast cells are involved, plays an important role in atopic dermatitis, since this disease is one of hypersensitivity reactions to a series of antigens, the patients or their family sometimes have other allergic disorders, and an increase in the serum IgE level is observed in many cases. However, anti-allergic agents that inhibit type I allergic reaction are ineffective or exhibit no therapeutic effect in atopic dermatitis, showing that the involvement of the type I reaction in the pathogenesis of this disease is only partial.
It has been reported, on the other hand, that the patients with atopic dermatitis show biphasic skin reaction, when they are exposed to the allergens (J. Allergy Clin. Immunol. 101, 222, 1998). This biphasic skin reaction is, for example, observed in the case of intradermal administration of an antigen such as Ascalis extract to animals sensitized to the same antigen (J. Immunol. 131, 1096, 1983). The first reaction, termed early-phase reaction, peaks 1 hr after the antigen challenge. The second reaction, late-phase reaction, is known to show the maximal response after 8 to 24 hours (Biol. Pharm. Bull. 18, 239, 1995). Early-phase reaction is suppressed by antagonists to histamine acceptors, suggesting that the reaction is induced by IgE and mast cells. In contrast, the mechanism of late-phase reaction is not necessarily clear, but is characterized by a remarkable infiltration of eosinophils in the skin (Int. Arch. Allergy Immunol. 113, 196, 1997), which is the typical histological feature observed in the patients with atopic dermatitis (J. Am. Acad. Dermatol. 24, 1101, 1991). Further, the severity of atopic dermatitis patients is known to be correlated with the serum level of ECP (eosinophil cationic proteins), and the number of peripheral eosinophils (Medicina 34, 220, 1997). Further, in recent years, it has been pointed out that the clinical symptoms of atopic dermatitis are extremely similar to the symptoms of contact dermatitis classified as a type IV allergic reaction (Medicina 34, 220, 1997). These findings suggest the possibility that a type IV allergic reaction is also involved in the mechanism of pathogenesis of the disease.
It is generally known that contact hypersensitivity reaction, the representative type IV allergic reaction, is induced by applying hapten such as DNFB (dinitrofluorobenzene) to the mice that had been sensitized once with the same hapten, but it has been recently reported that a type I allergic reaction is induced in addition to a type IV allergic reaction when repeatedly applying such a hapten to the skin (J. Invest. Dermatol. 105, 749, 1995). For example, by repeatedly applying hapten, the IgE level in the blood rises and the time-course of the reaction shifts to that of type I allergic reaction, by repeating the hapten challenge. In such an animal model, not only the transit response to hapten challenge, but also the baseline of skin thickness, the thickness before the hapten challenge, gradually increases, which seems to be a feature of chronic dermatitis. These findings suggest that the dermatitis induced by repeating application of hapten is thought to be useful as an animal model of atopic dermatitis (Anitex 10, 23, 1998).
Recently, it has been reported that NC/Nga mice spontaneously develop dermatitis similar to atopic dermatitis (Int. Immunol. 9, 461, 1997). NC/Nga mice that are maintained in conventional, non specific pathogen free environment begin to exhibit remarkable scratching behavior and erythema after about seven to eight weeks of age, then exhibit hemorrhaging or sores or ulceration of the skin with aging. Further, they exhibit symptoms resembling the clinical observations of atopic dermatitis in humans such as drying or thickening of the skin. Other strains of mice such as BALB/c do not suffer from similar dermatitis even if made to cohabitate with NC/Nga mice, suggesting that this dermatitis is considered specific to NC/Nga mice (Saishin Igaku (Latest Medicine), 53, 2848, 1998). Further, when raising these mice under specific paphogen free (SPF) environment, no skin abnormalities are observed at all, raising the possibility that some sort of environmental factors are involved in the onset of dermatitis in these mice. When NC/Nga mice raised under an SPF environment are repeatedly painted with hapten, only the delayed type hypersensitivity reaction called contact dermatitis is caused in the initial period of sensitization, but with the increase in sensitization, conditions similar to atopic dermatitis are observed (CRJ Letters 11, 1, 1998). Therefore, while the natural stimulant for the spontaneous dermatitis in these mice is still not clear, it is clear that repeated exposure to some sort of antigen under the natural environment is an important factor. Thus, these mice are extremely useful as a model for atopic dermatitis spontaneously caused by repeated exposure to an allergen that would be present in the air.
The most effective medicament for the treatment of atopic dermatitis is a steroid ointment (J. Allergy Clin. Immunol. 104, S123, 1999). Use of such steroid ointment, however, requires careful selection of the medicament used according to the location of application and timing. If the method of use is not appropriate, no effect will be manifested or the condition will conversely deteriorate. Further, when a steroid ointment is used over a long period, side effects such as atrophy and rosacea occur. Further, if stopping use of this medicament mid way, the phenomenon of rebound, that is, remarkable deterioration of the skin symptoms, is sometimes observed.
In addition to steroid ointment, histamine antagonists and anti-allergic agents have been used for treatment of atopic dermatitis. Histamine antagonists are effective in the sense of eliminating ichiness, but do not lead to a cure of this disease. Anti-allergic agents such as tranilast, ketotifen, oxatomide, and azelastine hydrochloride are ineffective against conditions of atopic dermatitis, or the effect is little, if any. This is believed to be due to the fact that these drugs have a suppressive action on a type I allergic reaction, but exhibit almost no effect on the actions of eosinophils or type IV allergic reaction (Jap. J. Pharmacol. 63, 73, 1993, Jap. J. Pharmacol. 51, 93, 1989). Recently ointment of tacrolimus, an immunosuppressive, has been developed as a medicament for treatment of atopic dermatitis (J. Allergy Clin. Immunol. 104, S126, 1999), but various side effects due to suppression of the immunoreaction by use of this medicament cannot be avoided. Taken together, it is difficult to say that any of the existing medicaments are sufficiently satisfactory in respect to efficacy and side effects, and development of a medicament superior in efficacy and safety is desirable.
On the other hand, chymase is a serine protease stored in mast cell granules, and widely present in tissue such as the skin, heart, vascular walls, intestines, etc. (Mast Cell Proteases in Immunology and Biology; Caughey, G. H., Ed; Marcel Dekker, Inc.; New York, 1995). It has been reported long ago that chymase acts on rat peritoneal mast cells and causes degranulation (J. Immunol. 136, 3812, 1986) and that a chymase inhibitor suppresses the Ig-E demiated mast cell degranulation (Biochem. Int. 10, 863, 1985) and has been pointed out that chymase is involved in the function of mast cells. Recently, it has been reported that administration of human chymase induces infiltation of leukocytes including eosinophils in mice as well as guinea pigs (Br. J. Pharmacol. 125, 1491, 1998), that human chymase acts on the precursor of IL-1β (Interleukin 1β) and converts it to active type IL-1β (J. Exp. Med. 174, 821, 1991), and that human chymase has the action of partially digesting membrane-bound stem cell factor (SCF) and converting it to soluble SCF (Proc. Natl. Acad. Sci. U.S.A. 94, 9017, 1997), etc. These findings suggest the possibility that chymase has some sort of role in allergic diseases such as atopic dermatitis. However, it is difficult to say that the pathophysiological role of chymase has been elucidated by these studies. At the present time, an energetic search is going on for substances which can inhibit the activity of chymase in vivo with the aim of clarifying the role of chymase in various diseases and the possibility of chymase inhibitors as pharmaceuticals.
There are chymase inhibitors such as low molecular weight chymase inhibitors such as shown in textbooks (Protease Inhibitors; Barrett et al., Eds; Elssevier Science B.V.; Amsterdam, 1996), α-keto acid derivatives reported as peptide type inhibitors (WO93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738), α,α-difluoro-β-keto acid derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-124691), tripeptide inhibitors (WO93-03625), phosphoric acid derivatives (Oleksyszyn et al., Biochemistry 30, 485, 1991), peptide like inhibitors such as trifluoromethylketone derivatives (WO96-33974, Japanese Unexamined Patent Publication (Kokai) No. 10-53579) and acetoamide derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication (Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No. 11-246437, WO99-41277, WO98-18794, WO96-39373), non-peptide type inhibitors such as triazine derivatives (Japanese Unexamined Patent Publication (Kokai) No. 8-208654 and Japanese Unexamined Patent Publication (Kokai) No. 10-245384), phenol ester derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87567), cephem derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87493), isoxazole derivatives (Japanese Unexamined Patent Publication (Kokai) No. 11-1479), imidazolidine derivatives (WO96-04248), hydantoin derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-31061), quinazoline derivatives (WO97-11941), etc. have been reported, but no satisfactory medicament or treatment method using inhibition of the activity of chymase as a strategy for treatment has yet been established.